In this study, we engineered liposomal indocyanine green (ICG) to maximize its photothermal effects while maintaining the fluorescence intensity. Various liposomal formulations of ICG were prepared ...by varying the lipid composition and the molar ratio between total lipid and ICG, and their photothermal characteristics were evaluated under near-infrared irradiation. We showed that the ICG dispersity in the liposomal membrane and its physical interaction with phospholipids were the main factors determining the photothermal conversion efficiency. In phototherapeutic studies, the optimized formulation of liposomal ICG showed greater anticancer effects in a mouse tumor model compared with other liposomal formulations and the free form of ICG. Furthermore, we utilized liposomal ICG to visualize the metastatic lymph node around the primary tumor under fluorescence imaging guidance and ablate the lymph node with the enhanced photothermal effect, indicating the potential for selective treatment of metastatic lymph node.
Objective:
Alzheimer disease (AD) brains are deficient in brain‐derived neurotrophic factor (BDNF), which regulates synaptic plasticity and memory. MicroRNAs (miRNAs) are ∼22‐nucleotide small ...noncoding RNAs that control a variety of physiological and disease processes. Here, we show that miR‐206 regulates BDNF and memory function in AD mice.
Methods:
Expression of miRNAs was analyzed in Tg2576 AD transgenic mice and human AD brain samples. Regulation of BDNF by a selected miRNA was validated by in silico prediction, target gene luciferase assay, and dendritic spine responses in neurons. AM206, a neutralizing inhibitor of miR‐206 (antagomir), was injected into the third ventricle of Tg2576 mice, after which memory function, synaptogenesis, neurogenesis, and target gene expression were assessed. For noninvasive delivery, antagomirs were administered intranasally.
Results:
The brains of Tg2576 mice and the temporal cortex of human AD brains had increased levels of miR‐206. This miRNA targeted BDNF transcripts, and AM206 prevented the detrimental effects of amyloid‐β42 on BDNF and dendritic spine degeneration in Tg2576 neurons. Injection of AM206 into the cerebral ventricles of AD mice increased the brain levels of BDNF and improved their memory function. In parallel, AM206 enhanced the hippocampal synaptic density and neurogenesis. Furthermore, intranasally administered AM206 also reached the brain and increased BDNF levels and memory function in AD mice.
Interpretation:
Our findings demonstrate a novel miRNA‐dependent regulation of BDNF in AD and suggest possible therapeutic approaches, such as noninvasive intranasal delivery of AM206. ANN NEUROL 2012;72:269–277.
Lipotoxic hepatocyte injury is a primary event in non-alcoholic steatohepatitis (NASH), but the mechanisms of lipotoxicity are not fully defined. Sphingolipids and free cholesterol (FC) mediate ...hepatocyte injury, but their link in NASH has not been explored. We examined the role of free cholesterol and sphingomyelin synthases (SMSs) that generate sphingomyelin (SM) and diacylglycerol (DAG) in hepatocyte pyroptosis, a specific form of programmed cell death associated with inflammasome activation, and NASH.
Wild-type C57BL/6J mice were fed a high fat and high cholesterol diet (HFHCD) to induce NASH. Hepatic SMS1 and SMS2 expressions were examined in various mouse models including HFHCD-fed mice and patients with NASH. Pyroptosis was estimated by the generation of the gasdermin-D N-terminal fragment. NASH susceptibility and pyroptosis were examined following knockdown of SMS1, protein kinase Cδ (PKCδ), or the NLR family CARD domain-containing protein 4 (NLRC4).
HFHCD increased the hepatic levels of SM and DAG while decreasing the level of phosphatidylcholine. Hepatic expression of
but not
was higher in mouse models and patients with NASH. FC in hepatocytes induced
expression, and
knockdown prevented HFHCD-induced NASH. DAG produced by SMS1 activated PKCδ and NLRC4 inflammasome to induce hepatocyte pyroptosis. Depletion of
prevented hepatocyte pyroptosis and the development of NASH. Conditioned media from pyroptotic hepatocytes activated the NOD-like receptor family pyrin domain containing 3 inflammasome (NLRP3) in Kupffer cells, but
knockout mice were not protected against HFHCD-induced hepatocyte pyroptosis.
SMS1 mediates hepatocyte pyroptosis through a novel DAG-PKCδ-NLRC4 axis and holds promise as a therapeutic target for NASH.
Acute rejection is hazardous to graft survival in kidney transplant recipients (KTRs). We aimed to identify novel biomarkers for early diagnosis of acute T cell-mediated rejection (TCMR) in urinary ...exosomes of KTRs.
Among 458 graft biopsies enrolled in a cross-sectional multicenter study, 22 patients with stable graft function (STA) who had not shown pathologic abnormality and 25 patients who diagnosed biopsy-proven TCMR were analyzed. We performed proteomic analysis using nano-ultra performance liquid chromatography-tandem mass spectrometry (nano-UPLC-MS/MS) to identify candidate biomarkers for early TCMR diagnosis on urinary exosomes. We confirmed the protein levels of each candidate biomarker by western blot analysis.
A total of 169 urinary exosome proteins were identified by nano-UPLC-MS/MS. Forty-six proteins showed increased expression in STA patients, while 17 proteins were increased in TCMR patients. Among them, we selected five proteins as candidate biomarkers for early diagnosis of TCMR according to significance, degree of quantity variance, and information from the ExoCarta database. We confirmed the proteomic expression levels of five candidate biomarkers by western blot analysis in each patient. Of all candidate biomarkers, tetraspanin-1 and hemopexin were significantly higher in TCMR patients (STA:TCMR ratio = 1:1.8, P = 0.009, and 1:3.5, P = 0.046, respectively).
Tetraspanin-1 and hemopexin were detected in KTR urine and could act as potential diagnostic proteins for TCMR.
The current study was designed to assess the inhibitory activity of Broussonetia papyrifera-derived polyphenols against 3-chymotrypsin-like and papain-like coronavirus cysteine proteases. The ...isolated compounds were broussochalcone B (1), broussochalcone A (2), 4-hydroxyisolonchocarpin (3), papyriflavonol A (4), 3′-(3-methylbut-2-enyl)-3′,4,7-trihydroxyflavane (5), kazinol A (6), kazinol B (7), broussoflavan A (8), kazinol F (9), and kazinol J (10). All polyphenols were more potent against papain-like protease (PL
pro
) than against 3-chymotripsin-like protease (3CL
pro
); therefore, we investigated their structural features that were responsible for this selectivity. Compound 4 was the most potent inhibitor of PL
pro
with an IC
50
value of 3.7 μM. The active compounds displayed kinetic behaviors, and the binding constants of their interaction with PL
pro
were determined from surface plasmon resonance analysis. Our results suggest B. papyrifera constituents as promising candidates for development into potential anti-coronaviral agents.
Medium cut-off (MCO) dialyzers help remove larger middle molecules associated with symptoms related to the accumulation of uremic retention solutes. We investigated the effect of an MCO dialyzer on ...the improvement of quality of life (QOL) in maintenance hemodialysis (HD) patients. Forty-nine HD patients with high-flux dialysis were randomly assigned to either an MCO (Theranova 400, Baxter) or a high-flux (FX CorDiax 80 or 60, Fresenius Medical Care) dialyzer and completed the study. QOL was assessed at baseline and after 12 weeks of treatment using the Kidney Disease Quality of Life Short Form-36, and pruritus was assessed using a questionnaire and visual analog scale. The reduction ratios of middle molecules were also evaluated. Laboratory markers, including serum albumin, did not differ between the two groups after 12 weeks. Removals of kappa and lambda free light chains were greater for MCO dialyzer than high-flux dialyzer. The MCO group had higher scores than the high-flux group in the domains of physical functioning and physical role (75.2 ± 20.8 vs. 59.8 ± 30.1, P = 0.042; 61.5 ± 37.6 vs. 39.0 ± 39.6, P = 0.047, respectively), and the MCO group had lower mean scores for morning pruritus distribution and the frequency of scratching during sleep (1.29 ± 0.46 vs. 1.64 ± 0.64, P = 0.034; 0.25 ± 0.53 vs. 1.00 ± 1.47, P = 0.023, respectively). MCO dialyzers may improve patient-reported outcomes, particularly the physical components of QOL and uremic pruritus, in patients with high-flux dialyzers.
The effect of chemical-composition modification on the chiroptical property of chiral organic ammonium cation-containing organic inorganic hybrid perovskite (chiral OIHP) is investigated. Varying the ...mixing ratio of bromide and iodide anions in S- or R-C6H5CH2(CH3)NH3)2PbI4(1–x)Br4x modifies the band gap of chiral OIHP, leading to a shift of the circular dichroism (CD) signal from 495 to 474 nm. However, it is also found that an abrupt crystalline structure transition occurs, and the CD signal is turned off when iodide-determinant phases are transformed into the bromide-determinant phase. To obtain CD in the wavelength range where the bromide-determinant phase is supposed to exhibit chiroptical activity, that is, <474 nm, S- or R-C12H7CH2(CH3)NH3 with a larger spacer group can be adopted; thus, the CD signal can be further blue-shifted to ∼375 nm. Here, we show that chemical-composition modification of chiral OIHP affects the chiroptical properties of chiral OIHP in two ways: (1) tuning the wavelength of CD by modulating the excitonic band structure and (2) switching the CD on and off by inducing a crystalline-structure change. These properties can be utilized for structural engineering of high-performance chiroptical materials for spin-polarized light-emitting devices and polarization-based optoelectronics.
Objectives
The objective of the study was to evaluate the radiographic changes in sinus mucosal thickness (SMT) in patients with mucosal thickening of odontogenic origin after maxillary molar ...extraction and lateral sinus augmentation with simultaneous surgical drainage and implant placement.
Materials and Methods
Forty‐six patients were included in this study. The changes in SMT were evaluated using cone‐beam computed tomography images produced at four time points: before extraction (T0), before surgery (T1), immediately after surgery (T2), and after prosthesis delivery (T3), and statistical differences between time points were analyzed. The changes in SMT and augmented bone height (ABH) regarding the reason of extraction, smoking, ostial patency, and the presence of postoperative sinusitis were also evaluated.
Results
Over time points, SMT gradually decreased (T0: 19.44 ± 9.22 mm, T1: 15.10 ± 8.89 mm, T2: 8.42 ± 6.01 mm, and T3: 4.16 ± 4.91 mm) (p < .05). Five out of 6 patients with ostial obstruction at T1 presented ostial patency at T3. Two patients developed postoperative sinusitis but recovered with medication. Ostial patency at T1, SMT at T1, and reason of extraction did not statistically significantly influence SMT at T3. SMT at T1 had no statistically significant impact on ABH change between T2 and T3.
Conclusion
Sinus mucosal thickness was gradually reduced by extraction of compromised teeth and drainage during lateral sinus augmentation. The drainage contributed more to the reduction in SMT.
HLA-incompatible (HLAi) and ABO-incompatible (ABOi) kidney transplantation (KT) has been on the increase over the last decade. However, there are wide variations in outcomes from these procedures. In ...this study we evaluated the graft and patient outcomes in incompatible KT and non-sensitized KT.
Patients who underwent KT between January 2012 and April 2018 were enrolled and reviewed. We divided kidney transplant recipients (KTRs) into five groups as follows: HLAi (n = 50); ABOi (n = 65); HLAi+ABOi (n = 5); control (n = 428); and living-donor control (LD control, n = 218). We compared the risk of rejection, graft function, graft survival, and patient survival between incompatible KTRs and control/LD control KTRs.
Although the incidence of active antibody-mediated rejection in HLAi group tends to be higher than in control and LD control groups (6.0% vs. 2.8%, P = 0.20; 6.0% vs. 3.7%, P = 0.44, respectively), the rejection-free survival, graft survival, and patient survival were not significantly different from those of the control and LD control groups in all three incompatible KT groups (all P>0.05). Graft function during the study period was also not different between incompatible KTRs and control/LD control groups (both P>0.05). Using Cox regression analysis, neither HLAi nor ABOi were risk factors for graft failure. Some infectious diseases such as urinary tract infection and cytomegalovirus infection were more common in the HLAi group than in the control/LD control group (both P<0.05), but only one infection-related death occurred in HLAi KTRs. Infection risks were similar in the ABOi and HLAi+ABOi groups compared to controls.
Our results showed favorable outcomes for incompatible KT after desensitization. Although desensitization therapy for incompatible KT has improved access to transplantation for KT candidates with high immunological risk, more clinical data are clearly needed.
Acute rejection (AR) is critical for long-term graft survival in kidney transplant recipients (KTRs). This study aimed to evaluate the efficacy of the integrated risk score of omics-based biomarkers ...in predicting AR in KTRs. This prospective, randomized, controlled, multicenter, pilot study enrolled 40 patients who recently underwent high-immunologic-risk kidney transplantation (KT). Five omics biomarkers were measured, namely, blood mRNA (three-gene signature), urinary exosomal miRNA (three-gene signature), urinary mRNA (six-gene signature), and two urinary exosomal proteins (hemopexin and tetraspanin-1) at 2 weeks and every 4 weeks after KT for 1 year. An integrated risk score was generated by summing each biomarker up. The biomarker group was informed about the integrated risk scores and used to adjust immunosuppression, but not the control group. The outcomes were graft function and frequency of graft biopsy. Sixteen patients in the biomarker group and nineteen in the control group completed the study. The mean estimated glomerular filtration rate after KT did not differ between the groups. Graft biopsy was performed in two patients (12.5%) and nine (47.4%) in the biomarker and control groups, respectively, with the proportion being significantly lower in the biomarker group (
= 0.027). One patient (6.3%) in the biomarker group and two (10.5%) in the control group were diagnosed with AR, and the AR incidence did not differ between the groups. The tacrolimus trough level was significantly lower in the biomarker group than in the control group at 1 year after KT (
= 0.006). Integrated omics biomarker monitoring may help prevent unnecessary or high-complication-risk biopsy and enables tailored immunosuppression by predicting the risk of AR in KTRs.
PDF
